Development of a New Approach for the Therapy of Prostate Cancer with SPOP Mutations

Advanced prostate cancer is treated with androgen deprivation, but mostpatients eventually progress and need new therapy. Recent genomic-exomicsequencing identified SPOP as the most frequently mutated gene in 6% - 15% ofprostate cancer. Based on the function of SPOP as a ubiquitin ligase in proteindegradation, it was hypothesized that loss-of-function mutations of SPOP led toaccumulation of SPOP substrates that enhance androgen receptor activity andfacilitate prostate cancer formation. SPOPsubstrates could thus be potential targets for treatment of androgen-sensitiveprostate cancer. PubMed and BLAST search identified that Gli, SRC-3, and AWP1are SPOP substrates, and that inhibition of PRK-1, a binding partner of AWP1,by lestaurtinib suppressed androgen receptor activity. LNCaP, PC3, DU145 and22RV1 prostate cancer cells were used to evaluate the effect of lestaurtinib.LNCaP cells, an androgen-sensitive prostate cancer cell line, were the mostsensitive. SRC-3 protein decreased when LNCaP cells were treated withlestaurtinib; whereas PRK-1 increased in nucleus after lestaurtinib treatment.These data suggest that lestaurtinib modulates SRC-3 and PRK-1 toinduced cell death in androgen-sensitive prostate cancer, and could be a usefulagent for future development for prostate cancer with SPOP mutations.